Mitochondrial homeostasis is required to maintain neuronal health and function, and its dysregulation plays prominent roles in rendering specific neural systems vulnerable. Recently we have found that the activation of the p38 mitogen-activated protein kinase (MAPK; the mammalian p38? ortholog) and the CREB like transcription factor ATF-7-mediated innate immune pathway in the intestine of C. elegans can protect its neurons from degeneration induced by mitochondrial dysfunction. The neuroprotective effects of p38MAPK/ATF-7 immunity activated in the gut occurs through the enhancement of mitophagy, and p38MAPK/ATF-7 activity in intestinal cells alone is sufficient to lower mitochondrial numbers, not only in intestinal cells, but also in neurons. Moreover, preliminary data obtained in our lab show that in C. elegans the peripheral increase in disease-related misfolded proteins can disrupt innate immune signaling pathways. Our central hypothesis, therefore, is that aging- and proteotoxicity-induced dysregulation of the immune system can disrupt mitochondrial homeostasis in neurons initiating or aggravating neurodegeneration. The objective of the proposed research is to determine how the p38MAPK/ATF-7-mediated innate immune pathway activated in the gut in C. elegans affects mitochondrial homeostasis in neurons. To do this, we will: Aim 1: Examine the role of the innate immune response in the maintenance of neurons upon Complex I dysfunction. Aim 2: Identify the immune mediators in the gut that affect neuronal health. Aim 3: Examine the role of peripheral proteotoxic antigens in disrupting immune signaling, leading to the accumulation of dysfunctional neuronal mitochondria. Our preliminary data show that the innate immune response modulates mitochondrial homeostasis in a cell non-autonomous manner, and is in turn can be inhibited by specific peripheral proteotoxic antigens. These studies therefore offer the novel possibility that immunosenescence is responsible for the accumulation of dysfunctional mitochondria, and could offer new insights into the role of proteotoxicity in the modulation of mitochondrial homeostasis.